Understanding the earliest events following mucosal transmission of HIV is fundamental to the development of an effective HIV vaccine; yet, these events are not well defined. We have shown previously that the infection of a4b7-expressing CD4+ T cells is one of these early events. Our approach in 2018 was to 1) further define the interaction between the virus and these cells, 2) assess the potential for signal transduction through a4b7 to promote viral replication in PBMCs from HIV-infected subjects, and 3) understand where infected a4b7- expressing CD4+ T cells reside in the early stages of infection. The interaction between gp120 and a4b7 holds the potential to impact the design of both vaccines as well as therapeutic strategies aimed at reducing viral reservoirs. Using an SIV/rhesus macaque model and immune PET/CT imaging, we have gained new insights into the role of this important subset of CD4+ T cells in the early stages of HIV infection.